tbuckley/cabot-search huggingface dataset:
The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma
Authors: Binhui Zhou, Ying Wang, Lichen Zhang, Xiaoyi Shi, Hesheng Kong, Mengjie Zhang, Yang Liu, Xia Shao, Zhilong Liu, Hongxu Song, Wushan Li, Xiaoxi Gao, Yanli Chang, Chenzhuo Dou, Wenzhi Guo, Shuijun Zhang, Xiaohong Kang, Jie Gao, Yinming Liang, Junfeng Zheng, Eryan Kong
Journal: Theranostics (2022)

Rationale: Protein palmitoylation is tightly related to tumorigenesis or tumor progression as many oncogenes or tumor suppressors are palmitoylated.AEG-1, an oncogene, is commonly elevated in a variety of human malignancies, including hepatocellular carcinoma (HCC).Although AEG-1 was suggested to be potentially modified by protein palmitoylation, the regulatory roles of AEG-1 palmitoylation in tumor progression of HCC has not been explored.Methods: Techniques as Acyl-RAC assay and point mutation were used to confirm that AEG-1 is indeed palmitoylated.Moreover, biochemical experiments and immunofluorescent microscopy were applied to examine the cellular functions of AEG-1 palmitoylation in several cell lines.Remarkably, genetically modified knock-in (AEG-1-C75A) and knockout (Zdhhc6-KO) mice were established and subjected to the treatment of DEN to induce the HCC mice model, through which the roles of AEG-1 palmitoylation in HCC is directly addressed.Last, HCQ, a chemical compound, was introduced to prove in principal that elevating the level of AEG-1 palmitoylation might benefit the treatment of HCC in xenograft mouse model. Results:We showed that AEG-1 undergoes palmitoylation on a conserved cysteine residue, Cys-75.Blocking AEG-1 palmitoylation exacerbates the progression of DEN-induced HCC in vivo.Moreover, it was demonstrated that AEG-1 palmitoylation is dynamically regulated by zDHHC6 and PPT1/2.Accordingly, suppressing the level of AEG-1 palmitoylation by the deletion of Zdhhc6 reproduces the enhanced tumor-progression phenotype in DEN-induced HCC mouse model.Mechanistically, we showed that AEG-1 palmitoylation adversely regulates its protein stability and weakens AEG-1 and staphylococcal nuclease and tudor domain containing 1 (SND1) interaction, which might contribute to the alterations of the RISC activity and the expression of tumor suppressors.For intervention, HCQ, an inhibitor of PPT1, was applied to augment the level of AEG-1 palmitoylation, which retards the tumor growth of HCC in xenograft model. Conclusion:Our study suggests an unknown mechanism that AEG-1 palmitoylation dynamically manipulates HCC progression and pinpoints that raising AEG-1 palmitoylation might confer beneficial effect on the treatment of HCC.
Association of Gout Polygenic Risk Score With Age at Disease Onset and Tophaceous Disease in European and Polynesian Men With Gout
Authors: Nicholas A. Sumpter, Riku Takei, Murray Cadzow, Ruth K. G. Topless, Amanda J. Phipps‐Green, Rinki Murphy, Janak de Zoysa, Huti Watson, Muhammad Qasim, Alexa S. Lupi, Abhishek Abhishek, Mariano Andrés, Tania O. Crișan, Michael Doherty, Lennart Jacobsson, Matthijs Janssen, Tim L. Jansen, Leo A. B. Joosten, Meliha Kapetanovic, Frédéric Lioté, Hirotaka Matsuo, Geraldine M. McCarthy, Fernando Perez‐Ruiz, Philip Riches, Pascal Richette, Edward Roddy, Blanka Stiburkova, Alexander So, Anne‐Kathrin Tausche, Rosa J. Torres, Till Uhlig, Tanya J. Major, Lisa K. Stamp, Nicola Dalbeth, Hyon K. Choi, Ana I. Vazquez, Megan P. Leask, Richard J. Reynolds, Tony R. Merriman
Journal: Arthritis & Rheumatology (2022)

To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout.A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease.The PRS was associated with earlier age at gout onset in men (β = -3.61 in years per unit PRS [95% confidence interval (95% CI) -4.32, -2.90] in European men; β = -6.35 [95% CI -8.91, -3.80] in East Polynesian men; β = -3.51 [95% CI -5.46, -1.57] in West Polynesian men) but not in women (β = 0.07 [95% CI -2.32, 2.45] in European women; β = 0.20 [95% CI -7.21, 7.62] in East Polynesian women; β -3.33 [95% CI -9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (β = -2.42 [95% CI -3.37, -1.46] and β = -6.80 [95% CI -10.06, -3.55], respectively) but not in West Polynesian men (β = -1.79 [95% CI -4.74, 1.16]).Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.
A combined polygenic score of 21,293 rare and 22 common variants improves diabetes diagnosis based on hemoglobin A1C levels
Authors: Peter Dornbos, Ryan Koesterer, Andrew Ruttenburg, Trang Nguyen, Joanne B. Cole, Aaron Leong, James B. Meigs, Jose C. Florez, Jerome I. Rotter, Miriam S. Udler, Jason Flannick
Journal: Nature Genetics (2022)
Socioeconomic Status and Ethnic Enclave as Risk Factors for Gastric Adenocarcinoma in Hispanic and Asian Americans, a California Cancer Registry Analysis
Authors: Christina P. Wang, Meg McKinley, Scarlett L. Gomez, Samir Gupta, Steven H. Itzkowitz, Shailja C. Shah, Ji Yoon Yoon, Annie Vu, Michelle Kang Kim
Journal: Clinical Gastroenterology and Hepatology (2022)
Delivery of aPD-L1 antibody to i.p. tumors via direct penetration by i.p. route: Beyond EPR effect
Authors: Mayu Yamamoto, Taiki Kurino, Reiko Matsuda, Haleigh Sakura Jones, Yoshito Nakamura, Taisei Kanamori, Atushi B. Tsuji, Aya Sugyo, Ryota Tsuda, Yui Matsumoto, Yu Sakurai, Hiroyuki Suzuki, Makoto Sano, Kensuke Osada, Tomoya Uehara, Yukimoto Ishii, Hidetaka Akita, Yasushi Arano, Akihiro Hisaka, Hiroto Hatakeyama
Journal: Journal of Controlled Release (2022)
Pharmacologic Treatment of Type 2 Diabetes in the U.S., Sweden, and Israel
Authors: Beini Lyu, Yingying Sang, Elizabeth Selvin, Alex R. Chang, G. Caleb Alexander, Cheli Melzer Cohen, Josef Coresh, Varda Shalev, Gabriel Chodick, Avraham Karasik, Juan-Jesus Carrero, Edouard L. Fu, Yang Xu, Morgan E. Grams, Jung-Im Shin
Journal: Diabetes Care (2022)

To characterize and compare glucose-lowering medication use in type 2 diabetes in the U.S., Sweden, and Israel, including adoption of newer medications and prescribing patterns.We used data from the National Health and Nutrition Examination Survey (NHANES) from the U.S., the Stockholm CREAtinine Measurements (SCREAM) project from Sweden, and Maccabi Healthcare Services (Maccabi) from Israel. Specific pharmacotherapy for type 2 diabetes between 2007 and 2018 was examined.Use of glucose-lowering medications among patients with type 2 diabetes was substantially lower in NHANES and SCREAM than in Maccabi (66.0% in NHANES, 68.4% in SCREAM, and 88.1% in Maccabi in 2017-2018). Among patients who took at least one glucose-lowering medication in 2017-2018, metformin use was also lower in NHANES and SCREAM (74.1% in NHANES, 75.9% in SCREAM, and 92.6% in Maccabi) whereas sulfonylureas use was greater in NHANES (31.5% in NHANES, 16.0% in SCREAM, and 14.9% in Maccabi). Adoption of dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter 2 inhibitors (SGLT2i) was slower in NHANES and SCREAM than in Maccabi. History of atherosclerotic cardiovascular disease, heart failure, reduced kidney function, or albuminuria was not consistently associated with greater use of SGLT2i or glucagon-like peptide 1 receptor agonists (GLP1RA) across the three countries.There were substantial differences in real-world use of glucose-lowering medications across the U.S., Sweden, and Israel, with more optimal pharmacologic management in Israel. Variation in access to care and medication cost across countries may have contributed to these differences. SGLT2i and GLP1RA use in patients at high risk was limited in all three countries during this time period.
Banoxantrone Coordinated Metal−Organic Framework for Photoacoustic Imaging‐Guided High Intensity Focused Ultrasound Therapy
Authors: Tingyu Sun, Jingnan Li, Chao Zeng, Chengyan Luo, Xirui Luo, Huanan Li
Journal: Advanced Healthcare Materials (2022)

Abstract Photoacoustic (PA) imaging with high spatial resolution has great potential as desired monitoring means in the high‐intensity focused ultrasound (HIFU) surgery of tumor. However, its penetration depth in the tissue is insufficient for achieving accurate intraoperative navigation, leading to residual tumor tissue. Nanomedicine provides a new opportunity for PA imaging to guide HIFU surgery. Studies have found that the hypoxic heterogeneity of tumor is effectively reversed by HIFU. Herein, a specific metal−organic framework nanosystem, constructed by coordination of banoxantrone (AQ4N) and Mn 2+ , is designed based on HIFU to reverse the hypoxic heterogeneity of tumors. It can provide exogenous light‐absorbing substances, thus improving the penetrability of PA imaging signal through the deep tissue and achieving clearer PA imaging for guiding HIFU surgery. In turn, AQ4N, in the hypoxic homogenous environment of the tumor provided by HIFU, is activated sequentially to specifically treat the residual hypoxic tumor cells. This combination treatment manifests higher tumor suppressors activation and lower expression of genes related to tumor progression. This strategy addresses the dissatisfaction with PA imaging‐guided HIFU therapy and is promising for translation into a clinical combination regimen.
CD8+ T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging
Authors: Tuğberk Kaya, Nicola Mattugini, Lu Liu, Hao Ji, Ludovico Cantuti-Castelvetri, Jianping Wu, Martina Schifferer, Janos Groh, Rudolf Martini, Simon Besson-Girard, Seiji Kaji, Arthur Liesz, Ozgun Gokce, Mikael Simons
Journal: Nature Neuroscience (2022)

Abstract A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8 + T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendrocyte loss, whereas T-cell checkpoint inhibition worsened the aging response. In addition, we identified a subpopulation of lymphocyte-dependent, IFN-responsive microglia in the vicinity of the CD8 + T cells in aging white matter. In summary, we provide evidence that CD8 + T-cell-induced, IFN-responsive oligodendrocytes and microglia are important modifiers of white matter aging.
Synthesis, preclinical evaluation and radiation dosimetry of a dual targeting PET tracer [<sup>68</sup>Ga]Ga-FAPI-RGD
Authors: Jie Zang, Xuejun Wen, Rong Lin, Xinying Zeng, Chao Wang, Mengqi Shi, Xueyuan Zeng, Jiaying Zhang, Xiaoming Wu, Xianzhong Zhang, Weibing Miao, Pengfei Xu, Zhide Guo, Jingjing Zhang, Xiaoyuan Chen
Journal: Theranostics (2022)

To enhance tumor uptake and retention, we designed and developed bi-specific heterodimeric radiotracers targeting both FAP and αvβ3, [ 68 Ga]Ga-FAPI-RGD.The present study aimed to evaluate the specificity, pharmacokinetics, and dosimetry of [ 68 Ga]Ga-FAPI-RGD by preclinical and preliminary clinical studies.Methods: FAPI-RGD was designed and synthesized with the quinoline-based FAPI-02 and the cyclic RGDfK peptide.Preclinical pharmacokinetics were determined in Panc02 xenograft model using microPET and biodistribution experiments.The safety and effective dosimetry of [ 68 Ga]Ga-FAPI-RGD was evaluated in 6 cancer patients, and compared with 2-[ 18 F]FDG imaging.Results: The [ 68 Ga]Ga-FAPI-RGD had good stability in saline for at least 4 h, and showed favorable binding affinity and specificity in vitro and in vivo.Compared to [ 68 Ga]Ga-FAPI-02 and [ 68 Ga]Ga-RGDfK, the tumor uptake and retention of [ 68 Ga]Ga-FAPI-RGD were very much enhanced than its monomeric counterparts at all the time points examined by microPET imaging.A total of 6 patients with various malignant tumors were prospectively enrolled.The effective dose of [ 68 Ga]Ga-FAPI-RGD was 1.94E-02 mSv/MBq.The biodistribution of [ 68 Ga]Ga-FAPI-RGD from 0 to 2 h after injection demonstrated rapid and high tumor uptake, prolonged tumor retention, and high tumor-to-background ratios (TBRs) which further increased over time.No significant difference in mean SUVmax of [ 68 Ga]Ga-FAPI-RGD and 2-[ 18 F]FDG was present in primary tumors (8.9±3.2 vs. 10.3 ± 6.9; p = 0.459). Conclusion:The dual targeting PET tracer [ 68 Ga]Ga-FAPI-RGD showed significantly improved tumor uptake and retention, as well as cleaner background over 68 Ga-labeled FAPI and RGD monospecific tracers.The first-in-human biodistribution study showed high TBRs over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.
Defining preferences over framed outcomes does not secure agents' rationality
Authors: Sarah A. Fisher
Journal: Behavioral and Brain Sciences (2022)

Abstract Bermúdez claims that agents think about framed outcomes, not outcomes themselves; and that seemingly incoherent preferences can be rational, once defined over framed outcomes. However, the agents in his examples know that alternative frames describe the same outcome, neutrally understood. This undermines the restriction of their preferences to framed outcomes and, in turn, the argument for rational framing effects.
Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT
Authors: C. Schuetz, J. Gerke, M. Ege, J. Walter, M. Kusters, A. Worth, J. A. Kanakry, D. Dimitrova, B. Wolska-Kuśnierz, K. Chen, E. Unal, M. Karakukcu, O. Pashchenko, J. Leiding, T. Kawai, P. J. Amrolia, D. Berghuis, J. Buechner, D. Buchbinder, M. J. Cowan, A. R. Gennery, T. Güngör, J. Heimall, M. Miano, I. Meyts, E. C. Morris, J. Rivière, S. O. Sharapova, P. J. Shaw, M. Slatter, M. Honig, P. Veys, A. Fischer, M. Cavazzana, D. Moshous, A. Schulz, M. H. Albert, J. M. Puck, A. C. Lankester, L. D. Notarangelo, B. Neven
Journal: Blood (2022)

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.
Extracellular vesicles: catching the light of intercellular communication in fibrotic liver diseases
Authors: Yijie Li, Jianzhi Wu, Runping Liu, Yinhao Zhang, Xiaojiaoyang Li
Journal: Theranostics (2022)

The increasing prevalence of fibrotic liver diseases resulting from different etiologies has become a major global problem for public health.Fibrotic liver diseases represent a redundant accumulation of extracellular matrix, dysregulation of immune homeostasis and angiogenesis, which eventually contribute to the progression of cirrhosis and liver malignancies.The concerted actions among liver cells including hepatocytes, hepatic stellate cells, kupffer cells, liver sinusoidal endothelial cells and other immune cells are essential for the outcome of liver fibrosis.Recently, a growing body of literature has highlighted that extracellular vesicles (EVs) are critical mediators of intercellular communication among different liver cells either in local or distant microenvironments, coordinating a variety of systemic pathological and physiological processes.Despite the increasing interests in this field, there are still relatively few studies to classify the contents and functions of EVs in intercellular transmission during hepatic fibrogenesis.This review aims to summarize the latest findings with regards to the cargo loading, release, and uptake of EVs in different liver cells and clarify the significant roles of EVs played in fibrotic liver diseases.
Optimal cardiometabolic health and risk of heart failure in type 2 diabetes: an analysis from the Look AHEAD trial
Authors: Kershaw V. Patel, Muhammad Shahzeb Khan, Matthew W. Segar, Judy L. Bahnson, Katelyn R. Garcia, Jeanne M. Clark, Ashok Balasubramanyam, Alain G. Bertoni, Muthiah Vaduganathan, Michael E. Farkouh, James L. Januzzi, Subodh Verma, Mark Espeland, Ambarish Pandey
Journal: European Journal of Heart Failure (2022)
Atezolizumab and Bevacizumab Combination Therapy and Sequential Conversion Hepatectomy for Advanced Fibrolamellar Hepatocellular Carcinoma Presenting Pseudoprogression
Authors: Ryota Matsuki, Naohiro Okano, Nobuhiro Hasui, Shohei Kawaguchi, Hirokazu Momose, Keiichiro Kitahama, Kiyotaka Nagahama, Masaharu Kogure, Yutaka Suzuki, Fumio Nagashima, Junji Shibahara, Hideaki Mori, Yoshihiro Sakamoto
Journal: Liver Cancer (2022)

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare a rare subtype of hepatocellular carcinoma. The IMbrave150 trial demonstrated that atezolizumab and bevacizumab therapy (ABT) has better treatment outcomes than sorafenib for advanced HCC. However, since patients with known FLHCC were excluded from this trial, the effects of ABT on FLHCC remain unknown. We report the first case of ABT for advanced FLHCC followed by hepatectomy presenting pseudoprogression of lymph node (LN) metastases which was pathologically proven after surgery. The patient was a 30-year-old man with advanced FLHCC and multiple LN metastases behind the pancreatic head, and ABT was introduced. After four courses of treatment, CT indicated a minor decrease in the intratumor vascularity of the liver tumor. However, the size of metastatic LNs increased. Subsequently, the patient presented with bloody stool, and colonoscopy revealed immune-related colitis caused by atezolizumab. Therefore, the fifth course was canceled. A right hemihepatectomy following percutaneous transhepatic portal vein embolization (PTPE) was performed to increase the future liver remnant volume. After PTPE, dynamic CT revealed an objective response to ABT; SD in RECIST 1.1 (7% increase in the LN size and no change of liver tumor), and PR in modified RECIST (47% decrease in the intratumor vascularity of the liver tumor and LNs). Three weeks after PTPE, right hemihepatectomy plus nodal dissection was successfully performed. Pathological findings revealed that approximately 60%–70% of the liver tumor and 70%–80% of the metastatic LNs were necrotic, indicating a good response to ABT. The increasing size of metastatic LNs that occurred during the treatment course was deemed pseudoprogression. Pseudoprogression can be found in patients with solid malignancies treated with immune checkpoint inhibitors, however, rarely occurs in HCC. The first response to metastatic LNs was observed 20 weeks after ABT initiation combined with an increase in nodal volume and a decrease in vascularity. In the updated data of the IMbrave150 trial, 19% of the first responses occurred after week 24. Physicians should consider that ABT may also be effective in FLHCC and may cause pseudoprogression before determining a treatment strategy.
Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism
Authors: Changpei Gan, Jing Wang, Alejandra Martínez-Chávez, Michel Hillebrand, Niels de Vries, Joke Beukers, Els Wagenaar, Yaogeng Wang, Maria C. Lebre, Hilde Rosing, Sjoerd Klarenbeek, Rahmen Bin Ali, Colin Pritchard, Ivo Huijbers, Jos H. Beijnen, Alfred H. Schinkel
Journal: Acta Pharmaceutica Sinica B (2022)

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1-/- ) mice, and a hepatic human CES1 transgenic model in the Ces1-/- background (TgCES1). Ces1-/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1-/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1-/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1-/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.